S-phase-coupled apoptosis in tumor suppression

Cho, Yong-Jig; Peng, Liang

doi:10.1007/s00018-011-0666-x

Cited by 15 publications

(15 citation statements)

References 124 publications

(176 reference statements)

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“…We have also quantitatively analyzed for apoptosis levels (Caspase-3) after Cl-amidine treatment via flow-cytometry, and see a dose-dependent decrease in proliferation and increase in apoptosis. Moreover, we also show that the cells arrest in S-phase after Cl-amidine treatment, thus leading to S-phase coupled apoptosis, which is a known response to DNA damage [44]. Taken together, the observed inhibitory effects of Cl-amidine on tumor growth may be due to the suppression of genes involved in oncogenesis and the activation of genes involved in apoptosis, though additional work is needed to define the mechanisms behind these potential relationships.…”

Section: Discussionmentioning

confidence: 91%

“…However, this was not surprising, as the effects of Cl-amidine are most pronounced after 3 days of treatment (data not shown). Taken together, it appears that Cl-amidine treatment after 4 days leads to S-phase coupled apoptosis, which is an intrinsic mechanism that prevents DNA replication of a damaged genome in a mammalian cell [44]. We also tested the effects of Cl-amidine on HER2/ERBB2 overexpressing cell lines BT-474 and SK-BR-3.…”

Section: Resultsmentioning

confidence: 99%

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Identification of PADI2 as a potential breast cancer biomarker and therapeutic target

et al. 2012

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BackgroundWe have recently reported that the expression of peptidylarginine deiminase 2 (PADI2) is regulated by EGF in mammary cancer cells and appears to play a role in the proliferation of normal mammary epithelium; however, the role of PADI2 in the pathogenesis of human breast cancer has yet to be investigated. Thus, the goals of this study were to examine whether PADI2 plays a role in mammary tumor progression, and whether the inhibition of PADI activity has anti-tumor effects.MethodsRNA-seq data from a collection of 57 breast cancer cell lines was queried for PADI2 levels, and correlations with known subtype and HER2/ERBB2 status were evaluated. To examine PADI2 expression levels during breast cancer progression, the cell lines from the MCF10AT model were used. The efficacy of the PADI inhibitor, Cl-amidine, was tested in vitro using MCF10DCIS cells grown in 2D-monolayers and 3D-spheroids, and in vivo using MCF10DCIS tumor xenografts. Treated MCF10DCIS cells were examined by flow-cytometry to determine the extent of apoptosis and by RT2 Profiler PCR Cell Cycle Array to detect alterations in cell cycle associated genes.ResultsWe show by RNA-seq that PADI2 mRNA expression is highly correlated with HER2/ERBB2 (p = 2.2 × 106) in luminal breast cancer cell lines. Using the MCF10AT model of breast cancer progression, we then demonstrate that PADI2 expression increases during the transition of normal mammary epithelium to fully malignant breast carcinomas, with a strong peak of PADI2 expression and activity being observed in the MCF10DCIS cell line, which models human comedo-DCIS lesions. Next, we show that a PADI inhibitor, Cl-amidine, strongly suppresses the growth of MCF10DCIS monolayers and tumor spheroids in culture. We then carried out preclinical studies in nude (nu/nu) mice and found that Cl-amidine also suppressed the growth of xenografted MCF10DCIS tumors by more than 3-fold. Lastly, we performed cell cycle array analysis of Cl-amidine treated and control MCF10DCIS cells, and found that the PADI inhibitor strongly affects the expression of several cell cycle genes implicated in tumor progression, including p21, GADD45α, and Ki67.ConclusionTogether, these results suggest that PADI2 may function as an important new biomarker for HER2/ERBB2+ tumors and that Cl-amidine represents a new candidate for breast cancer therapy.

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Section: Discussionmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Identification of PADI2 as a potential breast cancer biomarker and therapeutic target

et al. 2012

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“…In response to DNA damage, checkpoint surveillance mechanisms initiate signaling cascades which coordinate cell cycle arrest and facilitate DNA repair (Shiloh 2003, Bakkenist et al 2004, McGowan et al 2004). If these checkpoint surveillance mechanisms fail in neurons, neurodegeneration eventually occurs (Lavin 1999, Cho et al 2011). There has been a slow but steady accumulation of evidence of DNA damage in various neurodegenerative diseases (Robison et al 1984).…”

Section: Discussionmentioning

confidence: 99%

Effects of DSP4 on the Noradrenergic Phenotypes and Its Potential Molecular Mechanisms in SH-SY5Y Cells

et al. 2013

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Dopamine β-hydroxylase (DBH) and norepinephrine (NE) transporter (NET) are the noradrenergic phenotypes for their functional importance to noradrenergic neurons. It is known that in vivo N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) treatment induces degeneration of noradrenergic terminals by interacting with NET and depleting intracellular NE. However, DSP4’s precise mechanism of action remains unclear. In this study various biochemical approaches were employed to test the hypothesis that DSP4 down-regulates the expression of DBH and NET, and to determine molecular mechanisms that may be involved. The results showed that treatment of SH-SY5Y neuroblastoma cells with DSP4 significantly decreased mRNA and protein levels of DBH and NET. DSP4-induced reduction of DBH mRNA and proteins, as well as NET proteins showed a time- and concentration-dependent manner. Flow cytometric analysis demonstrated that DSP4-treated cells were arrested predominantly in the S-phase, which was reversible. The arrest was confirmed by several DNA damage response markers (phosphorylation of H2AX and p53), suggesting that DSP4 causes replication stress which triggers cell cycle arrest via the S-phase checkpoints. Moreover, the comet assay verified that DSP4 induced single-strand DNA breaks. In summary, the present study demonstrated that DSP4 down-regulates the noradrenergic phenotypes, which may be mediated by its actions on DNA replication, leading to replication stress and cell cycle arrest. These action mechanisms of DSP4 may account for its degenerative consequence after systematic administration for animal models.

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“…The DNA replication checkpoint (DRC) monitors chromosome replication during S-phase; if damage is detected, it promotes genome stability by shutting down cell cycle progression and elongation until the problem is repaired (reviewed in [42]). In the event that the damage is not repaired, the pathway in metazoans eventually causes apoptosis and the elimination of potentially carcinogenic cells from the population [43]. Key to this checkpoint is the ATR sensor kinase and Chk1/2 effector kinases; all, if mutated, promote genome instability leading to cancer [44].…”

Section: Introductionmentioning

confidence: 99%

The Mcm2-7 Replicative Helicase: A Promising Chemotherapeutic Target

Simon

Schwacha

2014

BioMed Research International

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Numerous eukaryotic replication factors have served as chemotherapeutic targets. One replication factor that has largely escaped drug development is the Mcm2-7 replicative helicase. This heterohexameric complex forms the licensing system that assembles the replication machinery at origins during initiation, as well as the catalytic core of the CMG (Cdc45-Mcm2-7-GINS) helicase that unwinds DNA during elongation. Emerging evidence suggests that Mcm2-7 is also part of the replication checkpoint, a quality control system that monitors and responds to DNA damage. As the only replication factor required for both licensing and DNA unwinding, Mcm2-7 is a major cellular regulatory target with likely cancer relevance. Mutations in at least one of the six MCM genes are particularly prevalent in squamous cell carcinomas of the lung, head and neck, and prostrate, and MCM mutations have been shown to cause cancer in mouse models. Moreover various cellular regulatory proteins, including the Rb tumor suppressor family members, bind Mcm2-7 and inhibit its activity. As a preliminary step toward drug development, several small molecule inhibitors that target Mcm2-7 have been recently discovered. Both its structural complexity and essential role at the interface between DNA replication and its regulation make Mcm2-7 a potential chemotherapeutic target.

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S-phase-coupled apoptosis in tumor suppression

Cited by 15 publications

References 124 publications

Identification of PADI2 as a potential breast cancer biomarker and therapeutic target

Identification of PADI2 as a potential breast cancer biomarker and therapeutic target

Effects of DSP4 on the Noradrenergic Phenotypes and Its Potential Molecular Mechanisms in SH-SY5Y Cells

The Mcm2-7 Replicative Helicase: A Promising Chemotherapeutic Target

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